Rachid Abaji1,2, Francesco Ceppi3, Swati Patel1, Vincent Gagné1, Chang J Xu1, Jean-François Spinella1, Antonella Colombini4, Rosanna Parasole5, Barbara Buldini6, Giuseppe Basso6, Valentino Conter4, Giovanni Cazzaniga7, Jean-Marie Leclerc1,8, Caroline Laverdière1,8, Daniel Sinnett1,8, Maja Krajinovic1,2,7. 1. Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, QC, H3T1C5, Canada. 2. Department of Pharmacology & Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, H3C 3J7, Canada. 3. Pediatric Hematology-Oncology Unit & Pediatric Hematology-Oncology Research Laboratory, Division of Pediatrics, Department of Woman-Mother-Child, University Hospital of Lausanne, 1004 Lausanne, Switzerland. 4. Department of Pediatrics, University of Milano-Bicocca, Ospedale S Gerardo, 20835 Monza, Italy. 5. Department of Pediatric Hemato-Oncology, Santobono-Pausilipon Hospital, 80129 Naples, Italy. 6. Department of Woman & Child Health, Laboratory of Haematology-Oncology, University of Padova, 35128 Padova, Italy. 7. Centro Ricerca Tettamanti, Department of Pediatrics, University Milano Bicocca, 20835 Monza, Italy. 8. Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC, H4A 3J1, Canada.
Abstract
AIM: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. PATIENTS & METHODS: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405). RESULTS: Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001). CONCLUSION: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.
AIM: To identify genetic markers associated with vincristine-induced peripheral neuropathy (VIPN) in childhood acute lymphoblastic leukemia. PATIENTS & METHODS: Whole-exome sequencing data were combined with exome-wide association study to identify predicted-functional germline variants associated with high-grade VIPN. Genotyping was then performed for top-ranked signals (n = 237), followed by validation in independent replication group (n = 405). RESULTS: Minor alleles of rs2781377/SYNE2 (p = 0.01) and rs10513762/MRPL47 (p = 0.01) showed increased risk, whereas that of rs3803357/BAHD1 had a protective effect (p = 0.007). Using a genetic model based on weighted genetic risk scores, an additive effect of combining these loci was observed (p = 0.003). The addition of rs1135989/ACTG1 further enhanced model performance (p = 0.0001). CONCLUSION: Variants in SYNE2, MRPL47 and BAHD1 genes are putative new risk factors for VIPN in childhood acute lymphoblastic leukemia.
Entities:
Keywords:
acute lymphoblastic leukemia; adverse drug reactions; association study; cancer; genetics; pharmacogenetics; polymorphism; vincristine-induced peripheral neuropathy; whole-exome sequencing
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